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Neuroimmunology

Crossed Networks

Stress produces unexpected effects on the connections between the nervous, immune and endocrine systems

MIGUEL BOYAYAN / JOSÉ MEDDAJoão Palermo-Neto, a veteran 59-year-old researcher, recognizes the surprise in the light of the results of an unprecedented experiment, to be published this month in the specialized magazine Neuroimmunomodulation: “I thought that nothing was going to happen”. In one of the laboratories of the School of Veterinary Medicine and Zootechny of the University of São Paulo (USP), where he lectures and coordinates a research group, healthy mice lived alongside animals with Ehrlich tumor, which leaves them with an enormous belly and can lead to death in less than two weeks. A few days after being put together, in pairs, the healthy mice started to behave like their sick companions: they would settle down into a corner of the cage, explore less the space around them, and feed themselves less than is usual. Besides this, their organic defenses dropped, measured by the quantity of defense cells – the white cells – in the blood.

In a second stage, the researchers injected tumor cells into healthy mice, and the symptoms of disease developed more rapidly in those animals that had been with the sick ones than those that had lived alongside their healthy companions. “I had never seen anything to indicate that the act of being together could alter the parameters for immunity”, comments Palermo, whose team will work hard in the next few months to discover if it through contact, smell, or some chemical stimulus that the healthy mice realized that their partners were ill.

This same research group had already observed in pregnant mice submitted to a situation of stress – electric shocks of a low intensity applied to their paws – an increase in anxiety, which was reflected in a greater sensitivity to Ehrlich’s tumor, compared with a group of animals that had not been exposed to the same stimulus.

Furthermore, there was a reduction in the activity of a kind of cells of the immune system, themacrophages, which quit engulfing and destroying the invading microorganisms with the habitual intensity – this task, called phagocytosis, is essential for activating other defense cells. In a study published in 2003, the group from USP noticed a reduction in phagocytosis also as a result of the prolonged use of diazepam, a drug used in medicines against anxiety. As a consequence, the organism may become more susceptible to infections generated by viruses and bacteria, which, for this reason alone, suggests redoubled cares in the use of these medications.

Little by little, these studies are showing how physical or emotional stress affects the organism, explaining with a growing wealth of details why herpes sores, for example, break out after a very worrying semester, or then why flu or an allergic crisis arises after a difficult exam, which has taken up months of study. These situations reflect the intricate connections between the three systems of the organism: the nervous system, the immune system and the endocrine.

The first, made up basically by billions of nerve cells (neurons) and by molecules that transmit the information (neurotransmitters), controls reactions, unconscious or conscious – from heartbeats to choosing one’s clothes in the morning. The immune system, made up mainly by the white blood cells, takes care of the defense of the organism, combating viruses, bacteria, protozoa, funguses, worms and foreign toxins, besides eliminating old or sick cells.

Finally, the endocrine system, with about a dozen glands that produce around 40 hormones, which regulate the transit of sugar and fat through the organism, or deepen the voices of boys at puberty. Acting in conjunction, the three systems form the triad that governs the organism. “One should no longer examine one without assessing the other two, because the three interact between themselves, 24 hours a day”, observes Wilson Savino, from the Oswaldo Cruz Foundation (Fiocruz), of Rio de Janeiro.

Chagas and Aids
In a study published in September 2003 in the European Journal of Immunology, Savino and his team demonstrated that the Trypanosoma cruzi, a protozoon that causes Chagas’s disease, damages one of the links that connect the three systems: the thymus, a gland the size of a pea located in the chest, between the lungs, behind the breastbone, and regarded as the maestro of the immune system. It is there that a kind of white cell is formed that is essential for combating viruses and bacteria, the so-called T lymphocytes, precisely because they develop initially in the thymus. From this gland, these cells follow on to the spleen and the ganglia, in which they finish maturing – it is only then that they are fit for combating invading microorganisms.

The power of the triad
A situation of extreme stress – a sudden leak of gas in the kitchen or the imminence of jumping with a parachute for the first time – sets off two mechanisms of the nervous system: one an immediate response, and another of a slower action. Milliseconds after the fright, a network of nerve fibers makes the suprarenal glands, located above the kidneys, produce the adrenaline and noradrenaline hormones. As a result, the heart begins to beat more quickly, the pupils dilate, and the blood irrigates the muscles more intensely – and the body mobilizes the energies for a reaction of fight or flight.

In parallel, the hypothalamus receives the information that something unusual is happening and releases a hormone called the corticotrophin releasing factor (CRF), which goes on to the pituitary gland, also at the base of the skull. Once activated, the pituitary gland secretes the adrenocorticotrophic hormone (ACTH). Falling into the bloodstream, the ACTH reaches the suprarenals and induces the release of another hormone, whose entry into the bloodstream takes place from two to four hours after the fright.

Under the action of the cortisol, the profile of the immune system: the so-called cellular response, carried out mainly by the macrophages and by white cells called neutrophils, gives way to the humoral response, based on the production of antibodies, released by the cells. In this change of guard, the organism may become more vulnerable to bacteria like the tuberculosis bacterium, whose elimination depends essentially on the cellular response.

The greatest problem lies with continuous stress, which mobilizes these hormones regularly and thus leaves the doors open for longer. Continually high concentrations of these hormones help to explain the fact of there being a 60% greater risk of an elderly person dying after the loss of the companion with whom he or she has lived for almost an eternity.

From the angle of neuroimmunology, dying of grief is not just a figure of speech, but a situation that is biochemically explainable. “Either the organism adapts, or the problems arise”, explains Sá-Rocha. According to him, the tendency is for situations that once seemed unbearable to stop perturbing the equilibrium of the body. “The higher levels of adrenaline of people who work in the Stock Exchange”, he gives as an example, “may no longer cause problems to those who are used to them, and, with time, they may even fall when faced by the same stressing stimulus.”

According to the work done at Fiocruz, the T. cruzi makes some T lymphocytes be released while still immature – hence not ready to fulfill their function satisfactorily. Furthermore, the parasite that affects 16 million people in Latin America, of which 6 million in Brazil, intensifies the production of molecules that accumulate in the thymus and hinders its workings.

After seeing, a few years ago, that the thymus atrophies as Chagas’s disease evolves, Savino’s team demonstrated that infection by T. cruzi also causes alterations to the hypothalamus and the pituitary gland, two regions of the brain that act in conjunction with the suprarenal glands and control the response of the immune systems, in situations of acute or chronic stress (please see box). “It is possible that something similar may occur in other acute infectious diseases, in which the atrophy of the thymus also occurs”, he says. “In rabies, for example, anomalies have now been seen in the so-called hypothalamus – pituitary axis.”

Advantage can already be taken from the knowledge about the connections between the three systems, to the benefit of human health. In a study accepted for publication in Neuroimmunomodulation, Savino presents the scientific grounding for the use of the human growth hormone (or hGH for short), as an auxiliary medicine in the treatment of diseases that undermine the immune system, like Aids. In transgenic mice that produce this hormone in above normal quantities, the hGH speeded up the exit of lymphocytes from the thymus, on which it acts directly, besides favoring their migration to the spleen and the lymph nodes (reservoirs of cells from the defense system) and their release into the blood. “In the animals”, says Savino, “we did not observe any collateral effects.”

If in the case of Aids a new prospect for treatment is opened up, the results reached by the team led by Thereza Quírico-Santos, from the Fluminense Federal University (UFF), and Soniza Leon, from the Federal University of Rio de Janeiro (UFRJ), have, for three years now, been helping to guide the strategies for treating another problem connected with the immune system, multiple sclerosis. This is a chronic inflammatory neurological disease of the nervous system that arises when – it is not known for sure why – the T lymphocytes decide to attack the myelin, a substance that covers the nerve fibers of the brain, the spinal cord and the optic nerves, giving rise to a picture of progressive incapacity in sight, movement or organic functions, which lead, for example, to urinary incontinence.

The researchers made the treatment more effective by means of two analyses made in the laboratory: the genetic profile, an indicator of the susceptibility of each person to the disease, and the so-called immunological reactivity, which indicates which pieces of the myelin are capable of activating the T lymphocytes against the nervous system. These two examinations indicate whether it is best to adopt antiinflammatories or immunomodulators, the two therapeutic options available today for controlling the disease At the end of the year, this group concluded a study showing that a communication molecule of the immune system – a cytokine – favors the movement of inflammatory cells to the nervous system.

“This work proves that the inflammatory process that destroys the myelin is continuous, even in patients without an outbreak”, Thereza explains. It is also a strong indication that it is fitting to treat the disease not only during the outbreaks, but even when there are no signs of the slow advance of the corrosion of the nerve fibers.In a recently concluded study, Luiz Carlos de Sá-Rocha, from USP, found different reactions in one same group of mice, in a direct association with hierarchy: there were the dominant ones, who lead the group, feed themselves first, and have access to the females before the other males; and the submissive ones, who live overshadowed by the dominant ones.

The researchers applied in the abdomen of each one of them a kind of sugar – a lipopolysaccharide – which triggers off similar reactions to those of a bacterium. And oddly enough, the dominant ones proved to be more sensitive – they stopped eating and prostrated themselves quietly in corner of the cage -, while the submissive ones showed themselves to be more resistant and kept themselves on the defensive with the leaders of the group. “Perhaps the mice from the submissive group have to make more effort to survive, and so become more resistant”, Sá-Rocha ponders.

Sensitive companions
The results so far obtained suggest that there may also be motivation for reacting, as if the animals allowed themselves to fall sick or not. In an attempt to apply the scientific results to the human universe, it would be a way of understanding why mothers manage to contain the symptoms of their own colds when their children have a bad cold, or why the companions of sick people tend to fall ill.

Cláudia Fernandes Laham, from the Psychology Division of USP’s Hospital and Clinics (HC) from USP, concluded last year a survey with 50 companions – or carers – of sick people attended to by the Interdisciplinary Home Assistance Nucleus (Nadi), a program with specialists who visit the sick in their homes. With an average age of 58 years, the carers were usually children (36%) or spouses (30%) of the sick person. More than half of them (62%) also showed health problems, such as muscular pains, high blood pressure or depression. “In the visits to the patients’ houses, it is not always easy to distinguish who is the sick person and who is the carer”, Cláudia reports. “Sometimes, the sick person is in better health.”

According to her study, taking care of a sick person implies freedom loss, solitude, tiredness and constant vigilance. “Any person who lives with the pain of another may think that they have to suffer as well, to maintain the relationship of love”, comments psychologist Niraldo de Oliveira Santos, from the Psychology Division of USP’s HC. When the sick person is closer – father, mother or child -, there is an even greater risk of symptoms breaking out in the companions similar or even identical because of the stronger ties of affection. “Identifying oneself with someone else’s suffering is a way of averting the feeling of blame for being healthy and for avoiding real or symbolic losses”, Niraldo says. But, as Cláudia found in her work, living with sick people also brings some gains, like the opportunity for taking care of somebody else or of feeling oneself productive with an occupation.

The Projects
1.
Neuroimmunomodulation; Modality Thematic Project; Coordinator João Palermo-Neto – FMVZ/USP; Investment R$ 716,213.73 (FAPESP)
2. Immunoreactivity in Multiple Sclerosis; Coordinator Thereza Quírico-Santos – UFF; Investment R$ 15,000 (CNPq) and R$ 6,000 (Capes)

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